Summary Advances in redirecting T cells to attack user-specified target cells using engineered chimeric antigen receptors (CAR-T) have led to the development of powerful cell-based therapeutics. Cellular immunotherapies possess several important advantages over traditional small molecule or antibody-based therapeutics, including the capacity to operate logically through integration of multiple signals, deliver customized therapeutic payloads, and activate or deactivate through engineered control. Here, we propose to adapt and exploit CAR-T technology as a therapeutic strategy in the setting of alcoholic liver disease (ALD). The forward engineering approach presented here leverages the principles of synthetic immunology to design, construct and test in vivo next-generation synNOTCH CAR-T, which are logically activated only in the presence of dual antigens displayed on the surface of Kupffer cells (KC), the liver resident macrophages. KC represent an excellent target cell population because of their pivotal role in driving liver inflammation, fibrosis and ALD progression to irreversible, end-stage cirrhosis and hepatocellular carcinoma. In Aim 2, we will evaluate the feasibility of utilizing the engineered CAR-T cells developed in Aim 1 to target and eliminate activated KC in vivo, using well established mouse models of alcoholic liver disease. We will interrogate whether our CAR-T can attenuate ALD disease progression, block fibrosis and steatosis, and restore liver function. We anticipate that these studies will establish the feasibility for the application of engineered CAR-T targeting KC as an effective therapeutic strategy for the treatment of alcoholic liver disease.